Alpha-phenyl tert butyl nitrone ##STR1## or "PBN") was identified in the 1970s as a useful analytical reagent to be used in conjunction with electron spin resonance ("ESR") to aid in the detection of free radicals. PBN was found to react with certain free radicals and generate a chemical species yielding a characteristic ESR spectrum and thus making it possible to determine the presence or absence of free radicals.
In the late 1970s and early 1980s the medical community began to focus on the roles played by free radicals in diseases such as heart attacks, strokes and the like. PBN was used increasingly in vitro to provide analytical evidence of the presence of free radicals in these settings. It was also later administered in vivo in animal models, again as an analytical adjunct in attempts to observe free radicals during ischemia simulations and the like.
In the mid 1980s, the first possible therapeutic effects of PBN were implied when severe trauma ischemia animal tests showed that PBN-treated animals were more likely to survive than controls.
On May 2, 1991, PCT patent application WO-91-05552 was published. This patent application, which in part corresponds to now-issued U.S. Pat. Nos. 5,825,032 and 5,036,097, described PBN and a family of PBN derivatives defined by the formula ##STR2## wherein X is phenyl or ##STR3## where R is H, ##STR4## or Z; or ##STR5## and n is a whole integer from 1 to 5 or ##STR6## and Y is tert-butyl or a hydroxylated or acetylated tert-butyl or a substituted phenyl. These compounds were proposed as pharmaceutical agents to treat the aftermath of stroke and other conditions reported to be associated with free radical damage.
In 1992 a second PCT patent application was filed directed to PBN and related compounds and their medical use. This application, based on prior U.S. patent application Ser. No. 716,952 (filed Jun. 18, 1991 abandoned on Apr. 26, 1993), was published on Dec. 23, 1992 as WO 92/22290. This 1992 publication provided two extremely broad and general disclosures. First, it attempted to describe as many disease states as possible which were associated with free radicals. These ranged from CNS conditions (including stroke, aging, migraine, etc.) through peripheral organ disease (including atherosclerosis, bed sores, wounds, and muscle overexertion) through UV exposure, to mention but a few highlights. Second, it attempted to list as many potential spin traps as possible.
In addition to a whole range of non-PBN materials, this application greatly expanded the definition of potentially useful PBN compounds to include PBN, and derivatives thereof of the formula ##STR7## wherein X is phenyl, imidazolyl, phenothiazinyl or ##STR8## n=1-5, preferably 1-3; R.sup.2 =independently (can vary within the molecule) halogen, alkyl, oxyalkyl, alkenyl, oxyalkenyl, OH, NH.sub.2, NHZ, NZ.sub.2, NO, ##STR9## --SO.sub.3 H, --OSO.sub.3 H, SH, --S(alkyl), --S(alkenyl), and haloalkyl, specifically including --CF.sub.3 ;
A=O or S; and PA1 Z is a C.sub.1 to C.sub.6 straight, branched, alkyl or cyclic group; and PA1 Y is a tert-butyl group that can be hydroxylated or acetylated at one or more positions; phenyl or ##STR10##
PBN was stated to be the most preferred compound at that time, being said to have no measurable effect on normal or uninjured cells, and a number of derivatives were also stated to be useful, including hydroxy derivatives, especially 2-, 3- or 4-hydroxyphenyl t-butyl nitrone and phenyl (mono-, di- or trihydroxy) tert-butyl nitrone; PBN esters, especially esters which release 2-, 3-, or 4-hydroxyphenyl t-butyl nitrone such as acetoxy derivative; 2-, 3-, or 4-carboxyphenyl t-butyl nitrone; phenyl hydroxybutyl nitrone; alkoxyl derivatives, especially alkoxyl derivatives which release 2-, 3-, or 4-hydroxyphenyl t-butyl nitrone, for example, the 2-, 3-, or 4-methoxyphenyl derivatives of PBN; and acetamide derivatives, especially acetamide derivatives which release 2-, 3-, or 4-aminophenyl t-butyl nitrone; diphenyl nitrone (PPN) and the analogous diphenyl nitrone derivatives; N-tert-butyl-.alpha.-(4-nitrophenyl) nitrone; and N-tert-butyl-.alpha.-(2-sulfophenyl) nitrone.